Prostanoids including various prostaglandins (PGs) and thromboxanes (TXs) are cyclooxygenase (COX) metabolites of C20-unsaturated fatty acids such as arachidonic acid, whereby the cyclooxygenases COX-1 and COX-2 catalyze the first committed step in the synthesis. Prostanoids exert a variety of actions in various tissues and cells. The most typical actions are the relaxation and contraction of various types of smooth muscles. They also modulate neuronal activity by either inhibiting or stimulating neurotransmitter release, sensitizing sensory fibers to noxious stimuli, or inducing central actions such as fever generation and sleep induction. Prostaglandins also regulate secretion and motility in the gastrointestinal tract as well as transport of ions and water in the kidney. They are involved in apoptosis, cell differentiation, and oncogenesis. Prostanoids also regulate the activity of blood platelets both positively and negatively and are involved in vascular homeostasis and hemostasis (Narumiya et al., 1999). These substances are synthesized in response to various stimuli in a variety of cells, released immediately after synthesis, and act in the vicinity of their synthesis (Smith and Langenbach, 2001).
Among prostanoids, the E type prostaglandins are most widely produced in the body and exhibit the most versatile actions through four different G-protein-coupled receptors designated EP1, EP2, EP3, and EP4, resulting in changes in the production of cAMP and/or phosphoinositol turnover, intracellular Ca2+ mobilization and agonist-induced changes in activities of downstream kinases (Coleman et al., 1994; Narumiya et al., 1999).
Stroke is the leading cause of serious, long-term disability and the second leading cause of death in the Western world, ranking after heart disease and before cancer (Donnan et al., 2008). Three million Americans are currently permanently disabled because of ischemic stroke, and 31% of stroke survivors need help caring for themselves, 20% need help walking, 71% have an impaired vocational capacity when examined an average of 7 years later, and 16% have to be institutionalized. Brain injury by transient complete global brain ischemia (cardiac arrest) and regional incomplete brain ischemia (ischemic stroke) afflicts a very large number of patients with death or permanent disability (White et al., 2000).
Cerebral ischemia and reperfusion engage multiple pathways involving loss of membrane integrity that quickly leads to neuronal injury and neuronal death. Free fatty acids, in particular free arachidonic acid, are released during cerebral ischemia as a consequence of the activity of both phospholipase C (activated by depolarization) and phospholipase A2 (activated by increased Ca2+i). Early during reperfusion, oxidative metabolism of arachidonate causes a burst of excess oxygen radicals, iron is released from storage proteins by superoxide-mediated reduction, and nitrogen monoxide is generated. Cyclooxygenases catalyze the addition of two molecules of O2 to an unsaturated fatty acid, like arachidonic acid, and produce prostaglandin PGG, which is rapidly peroxidized to prostaglandin PGH with concomitant release of oxygen radicals (White et al., 2000).
A neurotoxic effect of cyclooxygenase-2 (COX-2) has been demonstrated in rodent models of focal cerebral ischemia (Dore et al., 2003; Iadecola et al., 2001; Nagayama et al., 1999; Nogawa et al., 1998). Recent studies examining the mechanisms of COX-2 neurotoxicity have focused on the roles of individual prostaglandin signaling pathways downstream of COX-2. In vivo, the EP2 receptor exerts a significant cerebroprotective effect in both focal and permanent middle cerebral artery occlusion (MCAO) models (Liu et al., 2005; McCullough et al., 2004). Furthermore, the EP2 receptor exerts a cerebroprotective effect against N-methyl D-aspartate (NMDA) excitotoxicity in vivo (Ahmad et al., 2005). Thus, selected prostaglandin signaling systems downstream of COX-2 exert potent beneficial effects in the setting of ischemia.
The treatment of stroke includes preventive therapies using, for example, antihypertensive and anti-platelet drugs, which control and reduce blood pressure and, thus, reduce the likelihood of stroke. The development of anti-thrombotic agents such as tissue plasminogen activator (t-PA), which is currently the only FDA approved therapy for stroke, has provided a significant advancement in the treatment of ischemic stroke patients; however, to be effective, it is necessary to start treatment within a three-hours window after the onset of symptoms.
The development of therapeutic agents and effective methods of treatment for stroke and ischemic episodes in general is of great clinical interest, particularly for cases, where the three-hours window for the effective use of t-PA has been missed.